Metabolic interactions between tumor cells and the immunce system in GBM A potential Achilles heel of GBM for novel therapeutics

GBM 中肿瘤细胞与免疫系统之间的代谢相互作用是 GBM 新疗法的潜在致命弱点

• 批准号: 10673172
• 负责人: Loic Pierre Deleyrolle
• 金额: $ 41.7万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10673172
• 关键词: Affect; Apolipoprotein E; Biology; Brain Neoplasms; C57BL/6 Mouse; Cell Communication; Cell Compartmentation; Cell Cycle; Cell Lineage; Cell Shape; Cell physiology; Cells; Cellular Metabolic Process; Cellular biology; Clinical; Communication; Complex; Coupled; Dependence; Disease; Disease Outcome; Disease Progression; Environment; Exhibits; FABP3 gene; Fatty Acids; Flow Cytometry; Genetic; Glioblastoma; Glioma; Glucose; Goals; Growth; Heterogeneity; Image; Immune; Immune checkpoint inhibitor; Immune system; Immunological Models; In Vitro; Induction of Apoptosis; Intervention; Investigation; Knockout Mice; LCN2 gene; Label; Laboratories; Link; Lipids; Logic; Macrophage; Maintenance; Malignant Neoplasms; Mediating; Metabolic; Mitochondria; Modeling; Molecular; Morbidity - disease rate; Mus; Myeloid-derived suppressor cells; Nature; Outcome; Oxidative Phosphorylation; Pathway interactions; Patients; Phenotype; Play; Population; Proliferating; Recurrence; Recurrent disease; Regulatory T-Lymphocyte; Reporting; Research Design; Resistance; Role; Shapes; Signal Transduction; Sorting; Specimen; System; T-Lymphocyte; Technology; Testing; Therapeutic; Therapeutic Effect; Time; Transgenic Mice; Translating; Tumor Immunity; Tumor Promotion; Work; adipokines; aerobic glycolysis; anti-PD1 therapy; atorvastatin; cancer cell; cancer therapy; chemotherapy; clinically relevant; comparative; cytokine; digital; experimental study; genomic profiles; immune cell infiltrate; improved; in vivo; insight; intercellular communication; lipid biosynthesis; lipid metabolism; lipid transport; mortality; neoplastic cell; novel therapeutics; pharmacologic; programs; recruit; single-cell RNA sequencing; standard of care; temozolomide; therapeutic evaluation; therapy resistant; transcriptomics; tumor; tumor heterogeneity; tumor microenvironment; tumor progression; tumor-immune system interactions; tumorigenic; uptake

ABSTRACT Background: We recently revealed that glioblastoma (GBM) contain cell populations with distinct metabolic requirements, with fast-cycling cells (FCCs) harnessing aerobic glycolysis, and treatment-resistant slow-cycling cells (SCCs) preferentially engaging lipid metabolism. How the different tumor cells interact with immune cells and how this metabolic heterogeneity shapes the immune landscape in GBM has yet to be understood. Objectives/Hypothesis: The objectives of this study are to understand the mechanisms of communication in the tumor microenvironment, specifically to characterize the metabolic interactions between SCCs (a therapeutically resistant population that drive disease progression and recurrence) and the immune compartment. Here, we will investigate a model of intercellular communication within GBM where SCCs shape an immunosuppressive tumor milieu, which in turn assume metabolic support to SCCs by providing them with lipids, which are essential for SCC metabolism and function. Importantly, we will test multiple genetic and clinically amenable pharmacological approaches disrupting this metabolic interplay to antagonize GBM. Specific aims: Our specific aims will be 1) Dissect the relationship of SCCs with the tumor microenvironment, 2) Delineate how recruited immune suppressive cell mediate SCC-driven tumor progression, and 3) Establish that immune infiltrates provide metabolic support to SCCs by providing lipids. Study design: The link between tumor heterogeneity and tumor immune landscape in GBM will be deciphered with specific investigations of the metabolic interplay taking place between these cellular compartments. In aim 1, we will delineate the cell lineage (SCC vs FCC) relationship with immune infiltrates by investigating their genomic profile and spatial organization, using single cell RNA sequencing technology and GeoMx Digital Spatial Profiling, respectively. We will also evaluate the role of the specific adipokine, Lipocalin-2, in shaping the immune microenvironment. In aim 2 we will employ multiple approaches disrupting the macrophage, myeloid- derived suppressor cell, and regulatory T cell compartments, and compare the effect on survival, growth and chemotherapy sensitivity of SCCs and FCCs. In aim 3 the use of fluorescently labeled lipids combined with flow cytometry and time lapse imaging will enable the comparison of lipid transfer between immune cells, FCCs and SCCs. Finally, in vivo experiments will test the hypothesis that targeting lipid trafficking (inhibition of FABP3 or ApoE) or lipogenesis (statin treatment) provide therapeutic benefits by affecting SCCs and rendering the overall tumor more responsive to chemotherapy. Based on the recently reported synergistic effect of statins with immune checkpoint inhibitors, we will also evaluate the combination of statins with anti PD-1 therapy. Impact: Successfully completed, this project will validate therapeutically amenable approaches targeting metabolic communication to improve brain tumor associated morbidity and mortality.

抽象的 背景：我们最近透露，胶质母细胞瘤（GBM）包含具有独特代谢的细胞群体 要求，快速循环细胞（FCC）利用有氧糖酵解和耐药的慢速循环 细胞（SCC）优先吸引脂质代谢。不同的肿瘤细胞如何与免疫细胞相互作用 这种代谢异质性如何塑造GBM中的免疫景观尚待理解。 目标/假设：这项研究的目标是了解交流的机制 肿瘤微环境，特别是为了表征SCC之间的代谢相互作用（a 促进疾病进展和复发的治疗耐药种群和免疫区室。 在这里，我们将研究GBM内的细胞间通信模型，其中SCC塑造A 免疫抑制性肿瘤环境，进而为SCC提供代谢支持，从而为它们提供脂质， 这对于SCC代谢和功能至关重要。重要的是，我们将测试多个遗传和临床 正常的药理学方法破坏了这种代谢相互作用以对抗GBM。 具体目的：我们的具体目的是1）剖析SCC与肿瘤微环境的关系， 2）描述如何招募免疫抑制细胞介导SCC驱动的肿瘤进展，3）建立 免疫浸润物通过提供脂质为SCC提供代谢支持。 研究设计：GBM中的肿瘤异质性与肿瘤免疫景观之间的联系将被解密 对这些细胞室之间发生的代谢相互作用的具体研究。 在AIM 1中，我们将通过研究通过研究来描述细胞谱系（SCC与FCC）的关系 他们使用单细胞RNA测序技术和GEOMX Digital的基因组概况和空间组织 空间分析。我们还将评估特定脂肪因子Lipocalin-2的作用 免疫微环境。在AIM 2中，我们将采用多种方法破坏巨噬细胞，髓样 得出的抑制细胞和调节性T细胞室，并比较对生存，生长和 SCC和FCC的化学疗法敏感性。在AIM 3中，使用荧光标记的脂质与流量结合 细胞仪和时间流逝成像将使免疫细胞，FCC和FCC之间的脂质转移比较 SCCS。最后，体内实验将检验以下假设，即靶向脂质运输（抑制Fabp3或 APOE）或脂肪生成（他汀类药物治疗）通过影响SCC并提供整体来提供治疗益处 肿瘤对化学疗法的反应更快。基于最近报道的汀类药物的协同作用 检查点抑制剂，我们还将评估他汀类药物与抗PD-1治疗的组合。 影响：成功完成，该项目将验证针对性的治疗方法 代谢沟通以改善脑肿瘤相关的发病率和死亡率。